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310 Neurological observations (IV)
the mutated gene then there is no alternative normal gene, and they will therefore show the signs
of the disease.
7 Pill rolling dates from the time before mechanisation and quality control, when medication was
rolled into balls by hand to form tablets.
8 Substantia nigra (‘black substance’) is part of the basal ganglia responsible for reducing muscle
tone, among other functions.
9 Adduction should not be confused with abduction, where the limb is moved away from the
midline.
References
Anderson M.E. and Kiehn O. (2004) Motor systems. Current Opinion in Neurobiology, 14(6): 661–
664.
https://doi.org/10.1016/j.conb.2004.10.018
Bastian A.J. (1997) Mechanisms of ataxia. Physical Therapy, 77(6): 672–675.
Baxter S. (2008) Assessing pressure ulcer risk in long-term care using the Waterlow scale. Nursing
Older People, 20(7): 34–38.
Bentley P. (1999) Dementia demystied. Nursing Times, 95(45): 47–49.
Corcia P., Praline J., Vourch P. and Andres C. (2008) Genetics of motor neuron disorders. Revue
Neurologique, 164(2): 115–130.
Gasser T. and Kieburtz K. (2000) Huntington’s disease and Sydenham’s chorea. Movement Disor-
ders, 125(19): 2214–2217.
Hill-Smith I. and Johnson G. (2021) Little Book of Red Flags. National Minor Illness Centre,
Bedfordshire.
Lewko J., Demianiuk M., Krot E., Krajewska-Kułak E., Sierakowska M., Nyklewicz W. and Jankow-
iak B. (2005) Assessment of risk for pressure ulcers using the Norton scale in nursing practice.
Roczniki Akademii Medycznej w Bialymstoku Annales Academiae Medicae Bialostocensis,
50(Suppl. 1): 148–151.
Pomfrett C.J.D. (2005) Neural reexes. Anaesthesia and Intensive Care Medicine, 6(5): 145–150.
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15 Pharmacology and drug side effects,
interactions and allergies
• Introduction
• Pharmacology
• Drug side effects
• Drug interactions
• Drug allergies
• Key points
• Notes
• References
Introduction
Drugs can cause unwanted side (or toxic) effects and allergic reactions and may also
interact with each other when taken simultaneously. Such problems can cause health
problems and sometimes even death (Gottlieb 2001). Serious side effects have caused
patients to be reluctant to take their medication and sometimes being admitted to hospital
(Gutierrez 2010). Some drugs were withdrawn from medical use because the side effects
were unacceptable. Every effort is made to make medicines safe prior to their release.
Pharmacology
Pharmacology is the study of drugs and includes several more specic sciences, the main
ones being pharmacokinetics, pharmacodynamics and pharmacotherapeutics.
Pharmacokinetics (‘drug movement’) is the study of the way drugs move through the
body, from the point of entry to the point of exit. There are four stages:
• Absorption is the point of entry to the body, usually through oral, intramuscular and
intravenous administration.
• Distribution means transportation around the body, mostly in the blood.
• Metabolism can, for example, be chemical changes mostly in the liver.
• Elimination is the point of exit from the body, mostly through the kidneys.
DOI: 10.4324/9781003389118-15
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312 Pharmacology and drug side effects, interactions and allergies
Drug side effects, particularly drug interactions, can occur at any of these stages.
Pharmacodynamics is the study of how drugs work. Drugs work through multiple dif-
ferent ways depending on what they are prescribed for.
A useful way to distinguish pharmacokinetics from pharmacodynamics is to say the for-
mer is the way the body handles the drug and the latter is the way the drug handles the body.
Pharmacotherapeutics is the study of drugs used in clinical practice, including prescrib-
ing regimes and dosages, routes of administration, the storage of drugs and side effects.
The new science of pharmacogenetics puts the emphasis on prescribing ‘tailor made’
drug treatments to t individuals rather than a blanket treatment approach to t everyone.
It is not available yet with all treatments.
Two things have made this approach possible:
1 Advances in genetics. Everyone is a unique combination of genes. Even identical twins
have small variations in their genetic inheritance. Drugs and genes interact, if not
directly, then through the protein products of genes. By understanding the genetic
sequences of individuals, it has become possible to predict, to some extent, how a drug
will work in that individual and the possible outcome
2 Advances in drugs. One of the problems noted about the blanket approach to treat-
ment was that standard drug treatments are sometimes more affective in some people
than in others. Factors such as age, gender, race and tness all affect the way drugs
interact with the body at cellular level, inuencing how drugs do their job. Drug chem-
istry can be modied to t individual requirements. The source for new drugs is almost
unlimited, giving researchers many new compounds to explore and trial. The match-
ing of chemical compounds with an individual genetic pattern is becoming a reality.
Increases in computer power will make this a regular, everyday occurrence.
Pharmacokinetics
Most of our drugs can be administered by mouth. Oral drugs must be able to survive
potential digestion by catabolic
1
enzymes and wide pH variations, from gastric acidity to
bowel alkalinity. Some drugs must be given by injection, e.g. insulin, because these drugs
would not survive catabolic enzyme destruction if ingested. Drugs injected into a muscle
(i.e. intramuscular) will be absorbed slowly and that delays their activity over several
hours or longer. Drugs injected directly into the blood (i.e. intravenously) bypass absorp-
tion entirely and this is the fastest route for instant drug delivery.
Oral drugs are transported to the liver via the hepatic portal vein
2
prior to release into
general circulation (Figure 15.1). The liver carries out some metabolism on the drug prior
to its release into the general circulation. This is called rst-pass metabolism. This process
may render a portion of the drug dosage useless. The surviving drug is called the bioavail-
ability, i.e. it remains available for activity. If we consider the oral dosage of a drug as
100%, then rst pass metabolism may reduce this by 15%,
3
with 85% leaving the liver
unchanged (the bioavailability).
Most drugs are transported around the body in the blood stream. Whilst in the blood,
most are carried bound to blood proteins, notably albumin, the commonest blood protein
(see Chapter 4, Figure 4.1, page 67). Small quantities of drugs may be transported in the
lymphatic system but ultimately return to the blood.
The product of drug metabolism is a metabolite. Most metabolites are no longer active
as a drug and have been prepared for excretion (usually via the kidneys). They must then
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Pharmacology and drug side effects, interactions and allergies 313
Liver
Stomach
Spleen
Pancreas
Descending
Colon
Small
Intestines
Ascending
Colon
HPV
Figure 15.1 Hepatic portal vein (HPV) from the gut to the liver.
be transported to the kidney for this purpose via the hepatic vein (see footnote 2) and the
general circulation. In some cases, a drug metabolite is still active and continue to work
as the original drug, i.e. it contributes to the bioavailability. In a few cases the original
drug is not active until it has been metabolised. In this case the original (inactive) drug is
called a pro-drug, and the actual (active) metabolite is the drug itself.
Injected drugs initially bypass the liver, and they are not subjected to rst-pass metabo-
lism. The original dose administered is also the bioavailability.
Eventually all drugs, after activity, are metabolised in the liver and prepared for excre-
tion. How long drugs are active and remain in the blood depends on their half-life. The
half-life of different drugs varies widely. For example, drug X has a half-life of 2 hours.
The initial bioavailability is 100%. After 2 hours of metabolism (via the liver) and excre-
tion (via the kidneys) the drug bioavailability in circulation is reduced to 50%. After the
second 2-hour period of metabolism and excretion the bioavailability is further reduced
to 25%. The third 2-hour period reduces this further to 12.5% and so on (Figure 15.2).
Two things are shown by this:
1 The metabolism and excretion of the drug gradually slows down so only half of each
of the preceding 2-hour period is removed from circulation
2 Because each 2-hour period removes only half of the preceding bioavailability, it
becomes impossible to determine when zero is reached. Given enough time periods,
the values reached are incredibly small, far below the levels required to be active, and
it may therefore be necessary to take another dose.
Half-lives and rst pass metabolism are known for different drugs, and these are taken
into consideration when calculating drug dosage. Liver and kidney disease in some indi-
viduals will impinge on drug metabolism and/or excretion.
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Drug dose in plasma (mg/100ml)
10
9
8
7
6
5
4
3
2
1
1 2 3 4 5 6 7 8 910 11 12 1314
Hours after peak blood level
314 Pharmacology and drug side effects, interactions and allergies
Figure 15.2 T he half-life of a drug. This graph shows the elimination pattern of a drug (e.g. drug X,
with a half-life of two hours) from circulation. From peak plasma concentration (in this
case 10 mg/100 ml) the rst two hours sees an excretion of half the original concentra-
tion (down to 5 mg/100 ml). The second two-hour period sees an excretion of half this
new value (i.e. half the 5 mg/100 ml, down to 2.5 mg/100 ml). This pattern is repeated
every further two hours (i.e. removing half the concentration of the drug left at the start
of that two-hour period) until the drug is virtually zero.
Drugs with short half-lives will require regular repeated dosages throughout the day,
whilst those with long half-lives may only require a new dose daily or even longer. Drugs
that are slow release provide the new dosages continuously themselves throughout the
day with just one single administration daily, weekly or even monthly.
Pharmacodynamics
Pharmacodynamics describes how drugs work, i.e. their mode of action. It is beyond the
scope of this book to examine how individual drugs carry out their function.
Some important drugs are:
1 Antibiotics, which destroy bacterial infections by disrupting the structure or metabo-
lism of the organism whilst avoiding any harm to human cells. They can affect the nor-
mal bacteria of the gut when taken orally, causing cause bowel function side effects.
Some bacterial organisms can develop immunity to the antibiotics, the ‘super bugs’,
making these infections much harder to treat. Antibiotics do not work against viral
infections
4
(e.g. covid, the u or the common cold) which will usually resolve on their
own within ve to ten days. Long-term or life-threatening viral infections, e.g. HIV
(human immunodeciency virus) will require treatment with anti-viral drugs.
2 Analgesics, or pain-killing drugs, discussed in Chapter 12, page 257
3 Cardiac drugs, which are discussed in Chapter 2 (page 36) and Chapter 3 (page 57)
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Dose too high causing
side effects or even
toxicity
Increasing
Dose of drug
Therapeutic window
Dose adequate to be effective
without causing side effects
Dose too low to be effective
Pharmacology and drug side effects, interactions and allergies 315
4 Respiratory drugs, discussed in Chapter 5 (page 116)
5 Elimination drugs, discussed in Chapter 8 (page 177) and Chapter 9 (page 186).
6 Ophthalmic drugs, discussed in Chapter 13 (page 277).
A signicant number of drugs work by binding to receptors on cell surfaces. Receptors
are mostly proteins incorporated within the cell membrane with a binding site on the
surface. There are many different receptors, some controlling channels in the membrane
and therefore regulating substances entering through those channels. Others change the
cellular metabolism through intermediary chemicals (called messengers). Receptors acti-
vate when a natural body substance (called the ligand) binds to the receptor. Different
receptors have different ligands. Many drugs interrupt this binding process. Antagonists
are drugs that bind to – and block – the receptor so the ligand cannot bind. This stops the
action of the ligand. The opposite occurs when the drug is an agonist, which binds to the
receptor and acts like the ligand to activate the receptor. Receptors tend to be specic to
their own ligand, and for drugs to bind to a particular receptor it must have similar bind-
ing properties to those of the ligand, otherwise it would not bind. Side effects can occur
when the same receptor is widely distributed across several organs or body systems. In
this case, agonist or antagonist drugs given to affect the heart (for example) may also bind
to the same (or similar) receptors on other organs as well, causing unwanted effects.
Pharmacotherapeutics
The way drugs are used in clinical practice is pharmacotherapeutics. It covers many
aspects of clinical drug usage, including dosage, storage, prescribing, drug calculations,
routes of administration, side effects, drug interactions, record keeping etc.
The prescribed dose of the drug is based on the therapeutic window (Figure 15.3). This
is the window of dosage that will benet the patient whilst creating the least amount of
side effects. The lowest point of the window is the smallest dose that will have a benecial
Figure 15.3 The therapeutic window.
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316 Pharmacology and drug side effects, interactions and allergies
effect in the body, below which the effect is so small as to be of no value. The highest
point of the window is the dosage that has the maximum effect, above which side effects
(and possibly toxicity) will become a problem. It is the safe dosage window for prescrib-
ing (Figure 15.3). The ideal regime is to prescribe the drug at the lower end of the window
so there is opportunity to raise the dose if required, but this depends on what drug is
involved and the condition being treated.
Drug side effects
Drug side effects (or ‘toxic effects’) are dened as those effects that the drug has which are
unpleasant, unwanted and possibly harmful. They are mostly unrelated to the expected
function of the drug. There are examples of drug side effects which can be benecial or
therapeutic. They usually occur through a different mechanism separate from that for
which the drug was given i.e. a different pharmacodynamic activity.
Side effects involve almost every body system, but some systems are more affected
than others. The most likely effect would be with the system responsible for the drug’s
entry into the body, i.e. the rst point of contact. The digestive system is more affected
because most drugs are administered by mouth, so it is the rst system to contact the
medication and the rst system to process the drug. Topically administered drugs – i.e.
drugs in creams rubbed in through the skin – and subcutaneous injections, i.e. injected
just under the skin surface, can cause skin reactions.
Gastrointestinal (GI) side effects
Gastrointestinal (GI) side effects, such as nausea and vomiting, diarrhoea or constipa-
tion, are the most common side effects of drugs. Most GI side effects are mild and not
life-threatening but can be unpleasant and debilitating. Intravenous injections can also
cause GI side effects quite quickly by affecting the brain centres that control digestion
(see Chapter 9).
Nausea and vomiting
Nausea (feeling of sickness) and vomiting are common side effects of drugs because oral
drugs may irritate the mucosal lining of the stomach and because both oral and injected
drugs may activate the chemoreceptor trigger zone (CTZ) in the brainstem (see Chapter
9, Figure 9.4, page 189). Digestive mucosal irritation sends sensory stimuli to the brain-
stem via the vagus nerve (cranial nerve X; see Chapter 9, Figure 9.6, page 190). Chapter
9 discusses vomiting and the main drugs that cause it.
Diarrhoea and constipation
Diarrhoea is the passing of loose, even liquid stool, often multiple times per day. Consti-
pation is the retention of stools in the colon. The problems of constipation and diarrhoea
are discussed in Chapter 9, including morphine, and other drugs known for their consti-
pating side effects (see page 186). Drugs that cause diarrhoea include antibiotics since
these not only kill the bacteria causing the infection; they also kill the normal bacteria that
inhabit the gut (the intestinal ora; see faeces, Chapter 9).
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Pharmacology and drug side effects, interactions and allergies 317
Indigestion (dyspepsia)
Dyspepsia is a collection of stomach-related symptoms, including a feeling of bloating
and being overfull from excess gas, ‘heartburn’ (the burning pain caused by gastric acid
reuxing into the lower oesophagus) and upper abdominal pain and distension. Acidic
drugs, notably the non-steroidal anti-inammatory (NSAI) drugs, may induce dyspepsia –
and sometimes even gastric bleeding – by two different mechanisms. First, the acidic drug
molecules can cause direct irritation of the stomach mucosa which is already subjected
to a low pH (acidic) environment. Some aspirin products are enteric-coated which is a
protective coating over the tablet to reduce this gastric irritation. The coating dissolves
away once the tablet gets further down the digestive tract, where the environment is more
alkali. Second, the drug inhibits the enzyme cyclo-oxygenase (COX;
see page 258), which
occurs in two forms, COX1 and COX2. By blocking these enzymes, there is a loss of
production of certain prostaglandins (locally produced chemicals) that normally protect
the gastric mucosa against stomach acidity. With this protection lost, the stomach lining
is vulnerable, and becomes inamed and irritated by its own hydrochloric acid (HCl)
production. NSAIs that are COX2-specic are more gastric-protective with fewer GI side
effects (see page 316 Makins and Ballinger 2003).
Anorexia
Anorexia is loss of appetite, and this would affect patients experiencing side effects of
nausea and vomiting. The consequence of prolonged anorexia is weight loss and nutrient
deciencies, notably a loss of energy food (see Chapter 7).
The opioid drugs, such as morphine and diamorphine (heroin), are known to cause
appetite loss. They bind to opioid receptors in the brain called mu (µ) kappa (κ) and
delta (δ) (see Chapter 12, page 260, and drowsiness, page 324). Morphine activity on mu
receptors in particular suppresses brain function because these receptors are inhibitory,
i.e. they reduce brain function. Various parts of the brain are involved in appetite control
(
Blows 2022), and activation of mu receptors by opioid drugs will cause suppression of
these appetite systems.
Central nervous system (CNS) side effects
Drug side effects involving the central nervous system occur in many different types and
severity, dependent on which part of the brain is involved. Drugs must rst cross the
blood-brain barrier. This cellular barrier controls everything that crosses into the brain
from the blood, including drugs. Some drugs can cross without needing help, but others
do need help, via transport proteins, while some are unable to cross at all. Many drugs
do cross into the brain unaided and contribute to both the benecial and adverse effects
on the brain.
Antimuscarinic side effects
Acetylcholine (ACh), a neurotransmitter, binds to two acetylcholine receptor types: the
nicotinic and muscarinic receptors. They are named after two plant alkaloids, nico-
tine and muscarine, that bind to the receptors in laboratory conditions, although the
natural binding agent, i.e. the ligand, in the brain is acetylcholine. Acetylcholine is the
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Brainstem
ts
ptgf
Sacral
outflow
(PSP)
pgs
pgf
B
Cranial
outflow
(PSP)
Spinal
outflow
(SP)
S
p
i
n
a
l
c
o
r
d
A
318 Pharmacology and drug side effects, interactions and allergies
neurotransmitter found in the autonomic nervous system (ANS), i.e. the sympathetic and
parasympathetic systems. Both these parts of the ANS are two-neuronal systems passing
between the central nervous system and the target organ. The rst synapse between the
two neurons in both systems, are the pre-ganglionic synapses using acetylcholine. The
terminal synapse at the target organ for the parasympathetic system also uses acetylcho-
line. The terminal synapse at the target organ for the sympathetic system uses noradrena-
line (Figure 15.4).
Antimuscarinic drugs (i.e. muscarinic antagonists) block the muscarinic receptors
and therefore block activity of the parasympathetic system. They are used to treat a
range of conditions such as Parkinson disease and motion sickness and even in opti-
cal diagnostics (see blurred vision, page 320). Antimuscarinic side effects occur when
other drugs, i.e. those not used for their acetylcholine effects, coincidentally bind to the
Figure 15.4 The two parts of the autonomic nervous system (ANS). (A) The parasympathetic (PSP)
cranial outow comes from the brainstem (via cranial nerves III, VII, IX and X) and
the sacral outow comes from the lower end of the spinal cord. The sympathetic (SP)
outow comes from the thoracic section of the spinal cord. (B) Both systems involve
two neurons from the source to the terminal organ. The preganglionic synapse (pgs)
between the preganglionic bre (pgf) and post ganglionic bre (ptgf) uses acetylcholine
(ACh). The terminal synapse (ts) at the target organ uses acetylcholine in the parasym-
pathetic system and noradrenaline in the sympathetic system.
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LACHRYMAL
BRAINSTEM
CRANIAL
OUTFLOW
GLAND
PUPIL
SALIVARY
GLAND
HEART
SACRAL
OUTFLOW
BLADDER
F
E
D
C
B
A
S
P
I
N
A
L
C
O
R
D
BOWEL
Pharmacology and drug side effects, interactions and allergies 319
muscarinic receptor and prevent acetylcholine from binding. Antimuscarinic side effects
include (Figure 15.5):
• Dilated pupils and blurred vision, due to reduced parasympathetic control of the
intraocular eye muscles affecting the pupil size and the lens
• Urine retention happens when the parasympathetic bladder-emptying mechanism is
lost and the bladder retains urine
• Constipation is due to loss of the parasympathetic bowel-emptying mechanism and
the sympathetic takes over, retaining bowel content
• Dry mouth is due to changes in the salivary gland activity following loss of parasym-
pathetic stimulation
• Dry eyes due to the lack of lachrymal gland activity which normally lubricates the eyes
• Palpitations may occur if the parasympathetic (vagus nerve, cranial nerve X) input is
reduced to the heart and the sympathetic takes over, increasing the heart rate and force
of contraction.
Figure 15.5 The antimuscarinic drug side effects. These are caused by drugs blocking the mus-
carinic receptors in the parasympathetic system, and stopping acetylcholine (ACh)
from binding. The effects of this parasympathetic blockade are: (A) Dry eyes, (B) Pupil
dilation and blurred vision, (C) Dry mouth, (D) Palpitations (E) Urine retention and (F)
Constipation.
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